Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis
Authors: Giacomo Monti, Nikola Bradić, Matteo Marzaroli, Aidos Konkayev, Evgeny Fominskiy, Yuki Kotani, Valery V. Likhvantsev, Elena Momesso, Pavel Nogtev, Rosetta Lobreglio, Ivan Redkin, Fabio Toffoletto, Andrea Bruni, Martina Baiardo Redaelli, Natascia D’Andrea, Gianluca Paternoster, Anna Mara Scandroglio, Francesca Gallicchio, Mariano Ballestra, Maria Grazia Calabrò, Antonella Cotoia, Romina Perone, Raffaele Cuffaro, Giorgia Montrucchio, Vincenzo Pota, Sofia Ananiadou, Rosalba Lembo, Mario Musu, Simon Rauch, Carola Galbiati, Fulvio Pinelli, Laura Pasin, Fabio Guarracino, Giuseppe Santarpino, Felice Eugenio Agrò, Tiziana Bove, Francesco Corradi, Francesco Forfori, Federico Longhini, Maurizio Cecconi, Giovanni Landoni, Rinaldo Bellomo, Alberto Zangrillo, Silvia Ajello, Luca Baldetti, Alessandro Belletti, Giovanni Borghi, Martina Crivellari, Maria Fazio, Annalisa Franco, Giuseppe Giardina, Elena Moizo, Milena Mucci, Cristina Nakhnoukh, Pasquale Nardelli, Alessandro Ortalda, Nicola Pasculli, Vittorio Pazzanese, Marina Pieri, Valentina Plumari, Enrico Tomasi, Stefano Turi, Nicoletta Boffa, Marcella Parente, Marina Petrova, Anna Ilina, Amirkhan Kalov, Eugenio Garofalo, Antonio Caroleo, Giuseppe Saraco, Anna Trompeo, Luca Brazzi, Gabriele Sales, Eleonora Balzani, Luigi Vetrugno, Gabriella Marcuzzi, Chiara Millin, Giuseppe Pittella, Michelangelo Vitiello, Rosaria Vignale, Giulia Zingarelli, Elisa Zecchillo, Federico Dazzi, Erika Taddei, Maria Lidia Bologna, Assiya Kadralinova, Aigerim Yeltayeva, Maria Caterina Pace, Francesco Coppolino, Barbara Azzali, Alessia Mattei, Salvatore Sardo, Giannicola Aru, Lara Congiu, Vladimir Aliev, Elen​​​​​​a Khalikova, Daria Yavorovskaya, Massimiliano Greco, Carlo Leggieri, Paolo ME Seraglio, Andrea Della Selva, Filippo Pelagatti, Sabrina Boraso, Giulia Brizzi, Rubia Baldassarri, Stefano La Scala, Jasminka Persec, Sergio Torrente, Roberta Fiorito, Lian Kah Ti, Giuseppe Biondi-Zoccai, Umberto Benedetto, Fabrizio D’Ascenzo, Ludhmila A Hajjar
Journal: JAMA (2023)

Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.ClinicalTrials.gov Identifier: NCT03452839.